The nuclear hormone receptor superfamily is a very important target for drug development. Members of this group include androgen, estrogen, progesterone, and glucocorticoid receptors, the activity of which is controlled by ligand binding, as well as constitutive androstane and pregnane X receptors which have an essential role in drug metabolism. Nuclear hormone receptors regulate expression of their target genes, which control the essential metabolic reactions and differentiation processes of cells. Thus, disorders linked to nuclear receptors are of great clinical importance.
Androgens play an essential role in many physiological processes such as controlling the development and maintenance of muscle and skeletal mass as well as fertility in the male [Singh, S. M.; Gauthier, S.; Labrie, F. Curr. Med. Chem. 2000, 7211-7247]. Although non-steroidal AR agonists and antagonists are useful in the treatment of many disorders and diseases, there are no tissue specific selective androgen receptor modulators (SARMs) yet in clinical use. In particular, agonistic SARMs could be employed in the treatment of medical conditions such as hypogonadism caused by the deficiency of androgens and, especially, in the longterm hormone replacement therapy of aging people for the treatment of osteoporosis, loss of muscle mass or muscular power and sexual function disorders of both sexes. On the other hand, antiandrogenic compounds can be utilized against prostate cancer and hyperplasia, acne, cachexia and hirsutism, for example [Gao, W.; Bohl, C. E.; Dalton, J. T. Chem. Rev. 2005, 105, 3352-3370. Gao, W.; Reiser, P. J.; Coss, C. C.; Phelps, M. A.; Kaerbey, J. D.; Miller, D. D.; Dalton, J. T. Endocrinology 2005, 146, 4887-4897. Gao, W.; Kim, J.; Dalton, J. T. Pharmaceut. Res. 2006, 23, 1641-1658].
In conclusion, there is a need for small non-steroidal molecules which can act as agonists or antagonists for nuclear hormone receptors such as AR. We now describe a novel set of compounds which bind to AR, and inhibit its activity as assessed by the function of recombinant AR in reporter gene assays as well as by the analysis of endogenous AR target gene expression in human prostate cancer VCaP and LNCaP cells [Horoszewicz, J. S.; Leong, S. S.; Kawinski, E; Karr, J. P.; Rosenthal, H.; Chu, M.; Mirand, E. A.; Murphy, G. P. Cancer Res., 1983, 43, 1809-1818]. A further group of such compounds is for the first time disclosed to also inhibit the transcriptional activation by W741L-mutated AR in COS1-cells. The W741L mutation has been reported in prostate cancer patients and shown to render clinically most commonly used antiandrogen bicalutamide to an agonist [Hara, T.; Miyazaki, J.; Araki, H.; Yamaoka, M. Kanzaki, N.; Kusaka, M.; Miyamoto, M. Cancer Res. 2003, 63, 149-153].